Heterocyclically substituted phenylglycinolamides

ABSTRACT

The heterocyclically substituted phenylglycinolamides are obtained by reaction of heterocyclically substituted phenylacetic acids with appropriate phenylglycinols. The heterocyclically substituted phenylglycinolamides are suitable as active compounds in medicaments, in particular in antiatherosclerotically active medicaments.

The present invention relates to heterocyclically substitutedphenylglycinolamides, processes for their preparation and their use asmedicaments, in particular as antiatherosclerotic medicaments.

It is known that raised blood levels of triglycerides(hypertriglyceridaemia) and cholesterol (hypercholesterolaemia) areassociated with the genesis of atherosclerotic vascular wall changes andcoronary heart diseases.

A distinctly increased risk of the development of coronary heartdiseases moreover exists if these two risk factors occur in combination,which in turn is accompanied by an overproduction of apoliprotein B-100.There is therefore still a great need to make available activemedicaments for the control of atherosclerosis and coronary heartdiseases.

The compounds according to the invention are partially covered by thewidest scope of meaning of the publications DE 43 09 968, DE 43 02 956,DE 43 01 900, EP 565 086, EP 560 163, EP 560 162, EP 513 533 and DE 4200 954, without a pharmacological representative of this type beingmentioned there. The compounds mentioned here surprisingly show adecrease in or complete inhibition of the formation and/or the releaseof ApoB-100-associated lipoproteins from liver cells.

The present invention relates to heterocyclically substitutedphenylglycinolamides of the general formula (I) ##STR1## in which Arepresents quinolyl or

a radical of the formula ##STR2## in which R³, R⁴, R⁶ and R⁷ areidentical or different and denote hydrogen, phenyl, halogen, formyl,carboxyl, straight-chain or branched alkoxycarbonyl having up to 4carbon atoms or straight-chain or branched alkyl having up to 4 carbonatoms, which is optionally substituted by hydroxyl,

R⁵ denotes phenyl, straight-chain or branched alkyl, acyl or alkylthioeach having up to 6 carbon atoms or a group of the formula --CO--NR¹⁰R¹¹,

in which

R¹⁰ and R¹¹ are identical or different and denote hydrogen orstraight-chain or branched alkyl having up to 5 carbon atoms,

R⁸ and R⁹ are identical or different and denote hydrogen, straight-chainor branched alkyl or alkoxycarbonyl each having up to 6 carbon atoms ora radical of the formula --CO--R²,

in which

R¹² denotes morpholinyl or the radical of the formula ##STR3## R¹represents cycloalkyl having 3 to 8 carbon atoms, or representsstraight-chain or branched alkyl having up to 10 carbon atoms,

R² represents a radical of the formula ##STR4## in which R¹³ denoteshydrogen or a radical of the formula CH₂ --OH,

R¹⁴ denotes phenyl which is optionally substituted up to 3 timesidentically or differently by hydroxyl, halogen or straight-chain orbranched alkyl having up to 5 carbon atoms,

and their salts.

The heterocyclically substituted phenylglycinolamides according to theinvention can also be present in the form of their salts. In general,salts with organic or inorganic bases or acids may be mentioned here.

In the context of the present invention, physiologically acceptablesalts are preferred. Physiologically acceptable salts of the compoundsaccording to the invention can be salts of the substances according tothe invention with mineral acids, carboxylic acids or sulphonic acids.Particularly preferred salts are, for example, those with hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid,benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid,propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid,maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts ofthe compounds according to the invention which have a free carboxylgroup. Particularly preferred salts are, for example, sodium, potassium,magnesium or calcium salts, and also ammonium salts which are derivedfrom ammonia, or organic amines, such as, for example, ethylamine, di-or triethylamine, di- or triethanolamine, dicyclohexylamine,dimethylaminoethanol, arginine, lysine, ethylenediamine or2-phenylethylamine.

The compounds according to the invention can exist in stereoisomericforms which either behave as image and mirror image (enantiomers), orwhich do not behave as image and mirror image (diastereomers). Theinvention relates both to the enantiomers and to the diastereomers ortheir respective mixtures. These mixtures of the enantiomers anddiastereomers can be separated in a known manner into thestereoisomerically uniform constituents.

Preferred compounds of the general formula (I) according to theinvention are those

in which

A represents quinolyl or a radical of the formula ##STR5## in which R³,R⁴, R⁶ and R⁷ are identical or different and denote hydrogen, phenyl,fluorine, chlorine, bromine, formyl, straight-chain or branchedalkoxycarbonyl having up to 3 carbon atoms or straight-chain or branchedalkyl having up to 3 carbon atoms, which is optionally substituted byhydroxyl,

R⁵ denotes phenyl, straight-chain or branched alkyl, acyl or alkylthioeach having up to 5 carbon atoms or a group of the formula --CO--NR¹⁰R¹¹,

in which

R¹⁰ and R¹¹ are identical or different and denote hydrogen orstraight-chain or branched alkyl having up to 5 carbon atoms,

R⁸ and R⁹ are identical or different and denote hydrogen, straight-chainor branched alkyl or alkoxycarbonyl each having up to 5 carbon atoms ora radical of the formula --CO--R¹²,

in which

R¹² denotes morpholinyl or the radical of the formula ##STR6## R¹represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl, or represents straight-chain or branched alkyl having up to8 carbon atoms,

R³ represents a radical of the formula ##STR7## in which R¹³ denoteshydrogen or a radical of the formula CH₂ --OH,

R¹⁴ denotes phenyl which is optionally substituted up to 2 timesidentically or differently by hydroxyl, fluorine, chlorine, bromine orstraight-chain or branched alkyl having up to 3 carbon atoms,

and their salts.

Particularly preferred compounds of the general formula (I) according tothe invention are those

in which

A represents quinolyl or a radical of the formula ##STR8## in which R³,R⁴, R⁶ and R⁷ are identical or different and denote hydrogen, phenyl,chlorine, formyl, methoxycarbonyl, ethoxycarbonyl or methyl or ethyl,which is optionally substituted by hydroxyl,

R⁵ denotes phenyl, methylthio, acetyl, ethylthio or straight-chain orbranched alkyl having up to 4 carbon atoms or a group of the formula--CO--NR¹⁰ R¹¹,

in which

R¹⁰ and R¹¹ are identical or different and denote hydrogen orstraight-chain or branched alkyl having up to 3 carbon atoms,

R⁸ denotes methyl, methoxycarbonyl, ethoxycarbonyl or the radical of theformula ##STR9## and R⁹ denotes hydrogen, methyl, propyl or butyl,

and their salts.

Very particularly preferred compounds of the general formula (I) arethose which are listed in the following table.

    __________________________________________________________________________    1 #STR10##    A                  R.sup.1                              R.sup.2    __________________________________________________________________________     ##STR11##    2                  (R&S) cPent                              CH.sub.2 --C.sub.6 H.sub.5    3 #STR12##         (R&S) cPent                              5 #STR13##    3 #STR14##         (R&S) cPent                              CH.sub.2 --C.sub.6 H.sub.5    4 #STR15##         (R&S) cPent                              5 #STR16##    4 #STR17##         (dia A) cPent                              5 #STR18##    4 #STR19##         (dia B) cPent                              5 #STR20##    6 #STR21##         (R&S) cPent                              5 #STR22##    7 #STR23##         (R&S) cPent                              5 #STR24##    7 #STR25##         (dia A) cPent                              5 #STR26##    7 #STR27##         (dia B) cPent                              5 #STR28##    8 #STR29##         (dia A) cPent                              5 #STR30##    8 #STR31##         (dia B) cPent                              5 #STR32##    8 #STR33##         (dia A) cHept                              5 #STR34##    8 #STR35##         (dia B) cHept                              5 #STR36##    9 #STR37##         (R&S) cPent                              5 #STR38##    9 #STR39##         (R&S) cHept                              5 #STR40##    0 #STR41##         (R&S) cPent                              5 #STR42##    0 #STR43##         (R&S) cPent                              CH.sub.2 --C.sub.6 H.sub.5    0 #STR44##         (R&S) cHept                              5 #STR45##    0 #STR46##         (R&S) cHept                              CH.sub.2 --C.sub.6 H.sub.5    1 #STR47##         (R&S) cPent                              5 #STR48##    1 #STR49##         (R&S) cPent                              CH.sub.2 --C.sub.6 H.sub.5    1 #STR50##         (R&S) cHept                              5 #STR51##    1 #STR52##         (R&S) cHept                              CH.sub.2 --C.sub.6 H.sub.5    2 #STR53##         (R&S) cPent                              5 #STR54##    2 #STR55##         (R&S) cPent                              CH.sub.2 --C.sub.6 H.sub.5    2 #STR56##         (R&S) cHept                              5 #STR57##    2 #STR58##         (R&S) cHept                              CH.sub.2 --C.sub.6 H.sub.5    3 #STR59##         (R&S) cPent                              5 #STR60##    4 #STR61##         (R&S) cPent                              CH.sub.2 --C.sub.6 H.sub.5    4 #STR62##         (R&S) cHept                              5 #STR63##    3 #STR64##         (R&S) cHept                              CH.sub.2 --C.sub.6 H.sub.5    5 #STR65##         (R&S) cPent                              5 #STR66##    5 #STR67##         (R&S) cPent                              CH.sub.2 --C.sub.6 H.sub.5    5 #STR68##         (R&S) cHept                              5 #STR69##    5 #STR70##         (R&S) cHept                              CH.sub.2 --C.sub.6 H.sub.5    6 #STR71##         (R&S) cPent                              5 #STR72##    6 #STR73##         (R&S) cPent                              CH.sub.2 --C.sub.6 H.sub.5    6 #STR74##         (R&S) cHept                              5 #STR75##    6 #STR76##         (R&S) cHept                              CH.sub.2 --C.sub.6 H.sub.5    7 #STR77##         (R&S) cPent                              5 #STR78##    8 #STR79##         (R&S) cPent                              5 #STR80##    8 #STR81##         (R&S) cPent                              CH.sub.2 --C.sub.6 H.sub.5    8 #STR82##         (R&S) cHept                              5 #STR83##    9 #STR84##         (R&S) cPent                              CH.sub.2 --C.sub.6 H.sub.5    9 #STR85##         (R&S) cHept                              CH.sub.2 --C.sub.6 H.sub.5    0 #STR86##         (dia A) cPent    0 #STR87##         (dia B) cPent                              5 #STR88##    __________________________________________________________________________

A process for the preparation of the compounds of the general formula(I) according to the invention has additionally been found,characterized in that

carboxylic acids of the general formula (II) ##STR89## in which A and R¹have the meaning indicated above,

are reacted with amines of the general formula (III)

    H.sub.2 N--R.sup.2                                         (III)

in which

R² has the meaning indicated above,

in inert solvents and in the presence of bases and/or auxiliaries.

The process according to the invention can be illustrated by way ofexample by the following equation: ##STR90##

Suitable solvents for the amidation here are inert organic solventswhich do not change under the reaction conditions. These include ethers,such as diethyl ether or tetrahydrofuran, halogenohydrocarbons such asdichloromethane, trichloromethane, tetrachloromethane,1,2-dichloroethane, trichloroethane, tetrachloroethane,1,2-dichloroethylene or trichloroethylene, hydrocarbons such as benzene,xylene, toluene, hexane, cyclohexane or petroleum fractions,nitromethane, dimethylformamide, acetone, acetonitrile orhexamethylphosphoramide. It is also possible to employ mixtures of thesolvents. Dichloromethane, tetrahydrofuran, acetone anddimethylformamide are particularly preferred.

In general, bases which can be employed for the process according to theinvention are inorganic or organic bases. These preferably includealkali metal hydroxides such as, for example, sodium hydroxide orpotassium hydroxide, alkaline earth metal hydroxides such as, forexample, barium hydroxide, alkali metal carbonates such as sodiumcarbonate or potassium carbonate, alkaline earth metal carbonates suchas calcium carbonate, or alkali metal or alkaline earth metal alkoxidessuch as sodium or potassium methoxide, sodium or potassium ethoxide orpotassium tert-butoxide, or organic amines (trialkyl(C₁ -C₆)amines) suchas triethylamine or heterocycles such as 1,4-diazabicyclo 2.2.2!octane(DABCO), 1,8-diazabicyclo 5.4.0!undec-7-ene (DBU), pyridine,diaminopyridine, methylpiperidine or morpholine. It is also possible toemploy as bases alkali metals such as sodium and their hydrides such assodium hydride. Sodium and potassium carbonate and triethylamine arepreferred.

The base is employed in an amount from 1 mol to 5 mol, preferably from 1mol to 3 mol, relative to 1 mol of the compound of the general formula(II).

The reaction is in general carried out in a temperature range from 0° C.to 150° C., preferably from +20° C. to +110° C.

The reaction can be carried out at normal, elevated or at reducedpressure (e.g. 0.5 to 5 bar). In general, it is carried out at normalpressure.

The amidation can optionally also proceed via the activated stage of theacid halides, which can be prepared from the corresponding acids byreaction with thionyl chloride, phosphorus trichloride, phosphoruspentachloride, phosphorus tribromide or oxalyl chloride.

The abovementioned bases can optionally also be employed as acid-bindingauxiliaries for the amidation.

Suitable auxiliaries are also dehydrating reagents. These include, forexample, carbodiimides such as diisopropylcarbodiimide,dicyclohexylcarbodiimide orN-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride or carbonylcompounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as2-ethyl-5-phenyl-1,2-oxazolium-3-sulphonate or propanephosphonicanhydride or isobutyl chloroformate orbenzotriazolyloxy-tris-(dimethylamino)-phosphonium hexafluorophosphateor diphenyl phosphoramidate or methanesulphonyl chloride, if appropriatein the presence of bases such as triethylamine or N-ethylmorpholine orN-methylpiperidine, or dicyclohexylcarbodiimide andN-hydroxysuccinimide.

The acid-binding agents and dehydrating reagents are in general employedin an amount from 0.5 to 3 mol, preferably from 1 to 1.5 mol, relativeto 1 mol of the corresponding carboxylic acids.

The variation of functional groups such as, for example, hydrolysis,esterification and reduction, as well as separation of isomers and saltformation are carried out by customary methods.

The carboxylic acids of the general formula (II) are in the main new andcan be prepared by

reacting compounds of the general formula (IV) ##STR91## in which R¹ hasthe meaning indicated above,

T represents a typical leaving group such as, for example, chlorine,bromine, iodine, tosylate or mesylate, preferably bromine,

and

X represents (C₁ -C₄)-alkyl,

with compounds of the general formula (V)

    A--H                                                       (V)

in which

A has the meaning indicated

in inert solvents, if appropriate in the presence of a base, and thenhydrolysing the esters according to customary methods.

Suitable solvents for the process are customary organic solvents whichdo not change under the reaction conditions. These preferably includeethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethylether, or hydrocarbons such as benzene, toluene, xylene, hexane,cyclohexane or petroleum fractions, or halogenohydrocarbons such asdichloromethane, trichloromethane, tetrachloromethane, dichloroethylene,trichloroethylene or chlorobenzene, or ethyl acetate, triethylamine,pyridine, dimethyl sulphoxide, dimethylformamide,hexamethylphosphoramide, acetonitrile, acetone or nitromethane. It isalso possible to use mixtures of the solvents mentioned.Dimethylformamide and tetrahydrofuran are preferred.

In general, bases which can be employed for the process according to theinvention are inorganic or organic bases. These preferably includealkali metal hydroxides such as, for example, sodium hydroxide orpotassium hydroxide, alkaline earth metal hydroxides such as, forexample, barium hydroxide, alkali metal carbonates such as sodiumcarbonate or potassium carbonate, alkaline earth metal carbonates suchas calcium carbonate, or alkali metal or alkaline earth metal alkoxidessuch as sodium or potassium methoxide, sodium or potassium ethoxide orpotassium tert-butoxide, or organic amines (trialkyl(C₁ -C₆)amines) suchas triethylamine, or heterocycles such as 1,4-diazabicyclo 2.2.2!octane(DABCO), 1,8-diazabicyclo 5.4.0!undec-7-ene (DBU), pyridine,diaminopyridine, methylpiperidine or morpholine. It is also possible toemploy as bases alkali metals such as sodium or their hydrides such assodium hydride. Sodium hydride, potassium carbonate, triethylamine,pyridine and potassium tert-butoxide, DBU or DABCO are preferred.

In general, the base is employed in an amount from 0.05 mol to 10 mol,preferably from 1 mol to 2 mol, relative to 1 mol of the compound of theformula (IV).

The process according to the invention is in general carried out in atemperature range from -30° C. to +100° C., preferably from -10° C. to+60° C.

The process according to the invention is in general carried out atnormal pressure. However, it is also possible to carry out the processat elevated pressure or at reduced pressure (e.g. in a range from 0.5 to5 bar).

The compounds of the general formula (III) are known per se.

The compounds of the general formula (IV) are known or can be preparedin analogy to known methods.

The compounds of the general formula (V) are known or can be prepared inanalogy to known methods.

The compounds of the general formula (I) according to the invention havean unforeseeable spectrum of pharmacological action.

They can be used as active compounds in medicaments for the reduction ofchanges to vascular walls and for the treatment of coronary heartdiseases, cardiac insufficiency, brain function disorders, ischaemiccerebral disorders, apoplexy, circulatory disorders, disorders of themicrocirculation and thromboses.

The proliferation of smooth muscle cells furthermore plays a decisivepart in the occlusion of vessels. The compounds according to theinvention are suitable for inhibiting this proliferation and thuspreventing atherosclerotic processes.

The compounds according to the invention are distinguished by a loweringof the ApoB-100-associated lipoproteins (VLDL and its degradationproducts, such as, for example, LDL), of ApoB-100, of triglycerides andof cholesterol. They thus have useful pharmacological properties whichare superior compared with the prior art.

Surprisingly, the action of the compounds according to the inventionconsists first in a decrease in or complete inhibition of the formationand/or the release of ApoB-100-associated lipoproteins from liver cells,which results in a lowering of the VLDL plasma level. This lowering ofVLDL has to be accompanied by a lowering of the plasma levels ofApoB-100, LDL, triglycerides and of cholesterol; thus simultaneouslyseveral of the abovementioned risk factors which are involved invascular wall changes are lowered.

The compounds according to the invention can therefore be employed forthe prevention and treatment of atherosclerosis, obesity, pancreatitisand constipation.

1. Inhibition of the Release of ApoB-100-associated Lipoproteins

The test for detecting the inhibition of the release ofApoB-100-associated lipoproteins from liver cells was carried out invitro using cultured liver cells, preferably using cells of the humanline HepG2. These cells were cultured under standard conditions inmedium for the culture of eukaryotic cells, preferably in RPMI 1640using 10% foetal calf serum. HepG2 cells synthesize and secrete into theculture supernatant ApoB-100-associated lipoprotein particles which inprinciple are built up in a similar manner to the VLDL and LDL particleswhich are to be found in the plasma.

These particles can be detected using an immunoassay for human LDL. Thisimmunoassay is carried out using antibodies which have been inducedunder standard conditions against human LDL in rabbits. The anti-LDLantibodies (rabbit anti-LDL ABs) were purified by affinitychromatography on an immunosorbent using human LDL. These purifiedrabbit anti-LDL ABs are adsorbed on the surface of plastic. Expediently,this adsorption is carried out on the plastic surface of microtitreplates having 96 wells, preferably on MaxiSorp plates. IfApoB-100-associated particles are present in the supernatant of HepG2cells, then these can bind to the insolubilized rabbit anti-LDL ABs, andan immune complex results which is bound to the plastic surface.Non-bound proteins are removed by washing. The immune complex situatedon the plastic surface is detected using monoclonal antibodies whichhave been induced against human LDL and purified under standardconditions. These antibodies were conjugated with the enzyme peroxidase.Peroxidase converts the colourless substrate TMB into a coloured productin the presence of H₂ O₂. After acidification of the reaction mixturewith H₂ SO₄, the specific light adsorption at 450 nm is determined,which is a measure of the amount of ApoB-100-associated particles whichhas been secreted into the culture supernatant by the HepG2 cells.

Surprisingly, the compounds according to the invention inhibit therelease of ApoB-100-associated particles. The IC₅₀ indicates at whichsubstance concentration the light adsorption is inhibited by 50% incomparison to the control (solvent control without substance).

2. Determination of VLDL Secretion in vivo in the Hamster

The effect of the test substances on VLDL secretion in vivo isinvestigated in the hamster. To do this, golden hamsters areanaesthetized with Ketavet (83 mg/kg s.c.) and Nembutal (50 mg/kg i.p.)after premedication with atropine (83 mg/kg s.c.). When the animals havebecome reflex-free, the jugular vein is exposed and cannulated. 0.25ml/kg of a 20% strength solution of Triton WR-1339 in physiologicalsaline solution is then administered. This detergent inhibits thelipoprotein lipase and thus leads to a rise in the triglyceride level onaccount of an absent catabolism of secreted VLDL particles. Thistriglyceride rise can be used as a measure of the VLDL secretion rate.Blood is taken from the animals before and one and two hours afteradministration of the detergent by puncture of the retroorbital venousplexus. The blood is incubated for two hours at room temperature, thenovernight at 4° C. in order to finish clotting completely. It is thencentrifuged at 10,000 g for 5 minutes. In the serum thus obtained, thetriglyceride concentration is determined with the aid of a modifiedcommercially available enzyme test (Merckotest® triglyceride No. 14354).100 μl of serum are treated with 100 μl of test reagent in 96-holeplates and incubated at room temperature for 10 minutes. The opticaldensity is then determined at a wavelength of 492 nm in an automaticplate-reading apparatus (SLT spectra). Serum samples having too high atriglyceride concentration are diluted with physiological salinesolution. The triglyceride concentration contained in the samples isdetermined with the aid of a standard curve measured in parallel. Inthis model, test substances are administered intravenously eitherimmediately before administration of the detergent or orally orsubcutaneously before initiation of anaesthesia.

3. Inhibition of Intestinal Triglyceride Absorption in vivo (Rats)

The substances which are to be investigated for their triglycerideabsorption-inhibiting action in vivo are administered orally to maleWistar rats having a body weight of between 170 and 230 g. For thispurpose, the animals are divided into groups of 6 animals 18 hoursbefore administration of substance and the feed is then withdrawn fromthem. Drinking water is available to the animals ad libitum. The animalsof the control groups receive an aqueous tragacanth suspension or atragacanth suspension which contains olive oil. The tragacanth-olive oilsuspension is prepared using the Ultra-Turrax. The substances to beinvestigated are suspended in an appropriate tragacanth-olive oilsuspension, likewise using the Ultra-Turrax, directly before substanceadministration.

Blood is taken from each rat by puncture of the retroorbital venousplexus before stomach tube application to determine the basal serumtriglyceride content. The tragacanth suspension, the tragacanth-oliveoil suspensions without substance (control animals), or the substancessuspended in an appropriate tragacanth-olive oil suspension are thenadministered to the fasting animals using a stomach tube. Further takingof blood to determine the postprandial serum triglyceride rise isgenerally carried out 1, 2 and 3 hours after stomach tube application.

The blood samples are centrifuged and, after recovering the serum, thetriglycerides are determined photometrically using an EPOS analyser 5060(Eppendorf Geratebau, Netheler & Hinz GmbH, Hamburg). The determinationof the triglycerides is carried out completely enzymatically using acommercially available UV test.

The postprandial serum triglyceride rise is determined by subtraction ofthe triglyceride preliminary value of each animal from its correspondingpostprandial triglyceride concentrations (1, 2 and 3 hours afteradministration).

The differences (in mmol/l) at each time (1, 2 and 3 hours) are averagedin the groups, and the average values of the serum triglyceride rise(ΔTG) of the substance-treated animals are compared with the animalswhich only received the tragacanth-oil suspension.

The serum triglyceride course of the control animals which only receivedtragacanth is likewise calculated. The substance effect at each time (1,2 or 3 hours) is determined as follows and indicated in Δ% of theoil-loaded control. ##EQU1## Effect of 10 mg of test substance/kg ofbody weight p.o. on the triglyceride rise (Δ%) 2 h after a triglycerideloading in the serum of fasting rats. The serum triglyceride rise offat-loaded control animals relative to the serum triglyceride level oftragacanth control animals corresponds to 100%. n=6 animals per group.

Statistical analysis is carried out using Student's t-test after priorchecking of the variances for homogeneity.

Substances which at one time statistically significantly (p<0.05)decrease the postprandial serum triglyceride rise by at least 30%,compared with the untreated control group, are regarded aspharmacologically active.

4. Inhibition of VLDL Secretion in vivo (Rat)

The action of the test substances on VLDL secretion is likewiseinvestigated in the rat. To do this, Triton WR-1339 (2.5 mg/kg),dissolved in physiological saline solution, is administeredintravenously into the tail vein of rats of 500 mg/kg body weight.Triton WR-1339 inhibits lipoprotein lipase and thus leads by inhibitionof VLDL catabolism to a rise in the triglyceride and cholesterol level.These rises can be used as a measure of the VLDL secretion rate.

Blood is taken from the animals by puncture of the retroorbital venousplexus before and one and two hours after administration of thedetergent. The blood is incubated at room temperature for 1 h forclothing and the serum is recovered by centrifugation at 10,000 g for 20s. The triglycerides are then determined photometrically at a wavelengthof 540 nm by means of a commercially available coupled enzyme test(Sigma Diagnostics®, No. 339). Measurement is carried out with the aidof a likewise coupled enzyme test (Boehringer Mannheim®, No. 1442350) ata wavelength of 546 nm. Samples having triglyceride or cholesterolconcentrations which exceed the measuring range of the methods arediluted with physiological saline solution. The determination of therespective serum concentrations is carried out with the aid of standardseries measured in parallel. Test substances are administered orally,intravenously or subcutaneously immediately after Triton injection.

The invention additionally relates to the combination ofheterocyclically substituted phenylglycinolamides of the general formula(I) with a glucosidase and/or amylase inhibitor for the treatment offamiliar hyperlipidaemias, of obesity (adiposity) and of diabetesmellitus. Glucosidase and/or amylase inhibitors in the context of theinvention are, for example, acarbose, adiposine, voglibose, miglitol,emiglitate, MDL-25637, camiglibose (MDL-73945), tendamistate, AI-3688,trestatin, pradimicin-Q and salbostatin.

The combination of acarbose, miglitol, emiglitate or voglibose with oneof the abovementioned compounds of the general formula (I) according tothe invention is preferred.

The new active compounds can be converted in a known manner into thecustomary formulations, such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, non-toxic, pharmaceutically suitable excipients or solvents. Inthis connection, the therapeutically active compound should in each casebe present in a concentration of approximately 0.5 to 90% by weight ofthe total mixture, i.e. in amounts which are sufficient in order toachieve the dosage range indicated.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or excipients, if appropriate usingemulsifiers and/or dispersants, it being possible, for example, if wateris used as a diluent optionally to use organic solvents as auxiliarysolvents.

Administration is carried out in a customary manner, preferably orallyor parenterally, in particular perlingually or intravenously.

In the case of parenteral administration, solutions of the activecompound can be employed using suitable liquid excipient materials.

In general, it has proved advantageous in the case of intravenousadministration to administer amounts of approximately 0.001 to 1 mg/kg,preferably approximately 0.01 to 0.5 mg/kg, of body weight to achieveeffective results, and in the case of oral administration the dose isapproximately 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg, of bodyweight.

In spite of this, it may, if appropriate, be necessary to depart fromthe amounts mentioned, namely depending on the body weight or on thetype of administration route, on individual behaviour towards themedicament, the manner of its formulation and the time or interval atwhich administration takes place. Thus, in some cases it may be adequateto manage with less than the abovementioned minimum amount, while inother cases the upper limit mentioned has to be exceeded. In the case ofthe administration of larger amounts, it may be advisable to dividethese into several individual doses over the course of the day.

Abbreviations used:

Ph=phenyl

Me=methyl

Et=ethyl

cHex=cyclohexyl

Bn=CH₂ --C₆ H₅

Gly= ##STR92## C=cyclohexane EA=ethyl acetate

P=petroleum ether

STARTING COMPOUNDS Example I

tert-Butyl 2-cyclopentyl-2-4-(2-phenyl-imidazol-1-yl-methyl)phenyl!acetate ##STR93## 1.44 g (10mmol) of 2-phenylimidazole are dissolved in 10 ml of DMF, deprotonated(50° C.) using 330 mg (11 mmol) of NaH (80% strength) and the solutionis then treated with 3.5 g (10 mmol) of tert-butyl4-bromomethyl-2-cyclopentyl-acetate (DE 42 00 954 A1) and stirredovernight at RT. It is concentrated, the residue is dissolved in CH₂Cl₂, the solution is washed with H₂ O and concentrated and the residueis chromatographed on silica gel (cyclohexane/EA=8:2).

3.2 g (75%) are obtained as a colourless resin.

Example II

2-Cyclopentyl-2- 4-(2-phenyl-imidazol-1-yl-methyl)phenyl!acetic acid##STR94## 3.0 g (7 mmol) of the compound from Example I are dissolved in14 ml of dioxane, treated with 2 ml of conc. HCl and the solution isrefluxed for 5 h. It is concentrated, the residue is taken up in CH₂ Cl₂and the solution is washed with water. 2.6 g (96%) of the title compoundare obtained as an oil.

The examples listed in Table I are prepared in analogy to the procedureof Example II.

                                      TABLE I    __________________________________________________________________________    1 #STR95##    Ex. No.        A                 R.sup.1                                M.p. (° C.)                                      R.sub.f    __________________________________________________________________________    III        2 #STR96##        (R&S) cPent                                224    IV        3 #STR97##        (R&S) cPent                                194        4 #STR98##        (R&S) cPent    VI        5 #STR99##        (R&S) cPent 0.48 C/EA 1:1    VII        6 #STR100##       (R&S) cPent    VII        7 #STR101##       (dia A) cPent    IX        8 #STR102##       (R&S) cPent    X        9 #STR103##       (R&S) cPent                                172    XI        9 #STR104##       (R&S) cHept                                177    XII        0 #STR105##       (R&S) cPent 0.2 C/EA 1:1    XIII        0 #STR106##       (R&S) cHept                                206    XIV        1 #STR107##       (R&S) cPent 0.17 CH.sub.2 Cl.sub.2 /MeoH H 9:1    XV        1 #STR108##       (R&S) cHept 0.25 CH.sub.2 Cl.sub.2 MeOH 9:1    XVI        2 #STR109##       (R&S) cPent 0.3 C/EA 1:1    XVII        2 #STR110##       (R&S) cHept 0.32 C/EA 1:1    XVIII        3 #STR111##       (R&S) cPent                                203    XIX        3 #STR112##       (R&S) cHept                                192    XX        4 #STR113##       (R&S) cPent                                156    XXI        4 #STR114##       (R&S) cHept                                200    XXII        5 #STR115##       (R&S) cPent 0.45 CH.sub.2 Cl.sub.2 /MeOH 9:1    XXIII        6 #STR116##       (R&S) cPent    XXIV        6 #STR117##       (R&S) cHept    XXV        7 #STR118##       (R&S) cPent    XXVI        8 #STR119##       (dia A) cPent    XXVII        8 #STR120##       (dia B) cPent    __________________________________________________________________________

PREPARATION EXAMPLES Example 1

2-Cyclopentyl-N-(2-hydroxy-1-(R)-phenylethyl)-2-4-(2-phenylimidazol-1-yl-methyl)phenyl!acetamide ##STR121## 1.08 g (3mmol) of the compound from Example II are dissolved in 30 ml of CH₂ Cl₂with 0.412 g (3 mmol) of R-(-)-2-phenylglycinol (Aldrich), then 0.446 g(3.3 mmol) of 1-hydroxy-1H-benzotriazole hydrate (Aldrich) are added.After addition of 662 mg (3.45 mmol) ofN'-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (Aldrich)and 0.8 ml of triethylamine, the mixture is stirred at RT overnight. Itis diluted with CH₂ Cl₂, washed once each with NH₄ Cl solution andNaHCO₃ solution, dried and concentrated in a rotary evaporator. Theresidue is chromatographed using cyclohexane/ethyl acetate (1:1).

Yield: 1.46 g (98%). R_(f) =0.17 (cyclohexane/ethyl acetate=1:1)

The compounds listed in Table 1 are prepared via the correspondingprecursors (analogously to Examples I and II) in analogy to theprocedure of Example 1:

                                      TABLE 1    __________________________________________________________________________    9 #STR122##    Ex. No.        A                 R.sup.1                                 R.sup.2                                     M.p. (° C.)                                           R.sub.f    __________________________________________________________________________        0 #STR123##       (R&S) cPent                                 N-Bn      0.12 C/EA 4:6    3        1 #STR124##       (R&S) cPent                                 R-Gly                                     175    4        1 #STR125##       (R&S) cPent                                 Bn        0.25 C/EA 7:3    5        2 #STR126##       (R&S) cPent                                 R-Gly     0.5 CH.sub.2 Cl.sub.2 /CH.sub.3 OH                                           10:1    6        2 #STR127##       (dia A) cPent                                 R-Gly     0.5 CH.sub.2 Cl.sub.2 /CH.sub.3 OH                                           10:1    7        2 #STR128##       (dia B) cPent                                 R-Gly     0.5 CH.sub.2 Cl.sub.2 /CH.sub.3 OH                                           10:1    8        3 #STR129##       (R&S) cPent                                 R-Gly                                     154    9        4 #STR130##       (R&S) cPent                                 R-Gly     0.39 P/EA 1:1    10        4 #STR131##       (dia A) cPent                                 R-Gly     0.43 P/EA 1:1    11        4 #STR132##       (dia B) cPent                                 R-Gly     0.35 P/EA 1:1    12        5 #STR133##       (dia A) cPent                                 R-Gly     0.16 P/EA 4:6    13        5 #STR134##       (dia B) cPent                                 R-Gly     0.09 P/EA 4:6    14        5 #STR135##       (dia A) cHept                                 R-Gly     0.24 P/EA 4:6    15        5 #STR136##       (dia B) cHept                                 R-Gly     0.12 P/EA 4:6    16        6 #STR137##       (R&S) cPent                                 R-Gly     0.35 P/EA 1:1    17        6 #STR138##       (R&S) cHept                                 R-Gly     0.44 P/EA 1:1    18        7 #STR139##       (R&S) cPent                                 R-Gly     0.58 C/EA 4:6    19        7 #STR140##       (R&S) cPent                                 Bn  105-106    20        7 #STR141##       (R&S) cHept                                 R-Gly     0.08 C/EA 4:6    21        7 #STR142##       (R&S) cHept                                 Bn        0.2 C/EA 4:6    22        8 #STR143##       (R&S) cPent                                 R-Gly     0.28 C/EA 1:1    23        8 #STR144##       (R&S) cPent                                 Bn  119-120    24        8 #STR145##       (R&S) cHept                                 R-Gly     0.32 C/EA 1:1    25        8 #STR146##       (R&S) cHept                                 Bn  168-169    26        9 #STR147##       (R&S) cPent                                 R-Gly     0.11 CH.sub.2 Cl.sub.2 /CH.sub.3                                           OH 9:1    27        9 #STR148##       (R&S) cPent                                 Bn        0.25 CH.sub.2 Cl.sub.2 /CH.sub.3                                           OH 9:1    28        9 #STR149##       (R&S) cHept                                 R-Gly     0.23 CH.sub.2 Cl.sub.2 /CH.sub.3                                           OH 9:1    29        9 #STR150##       (R&S) cHept                                 Bn        0.19 CH.sub.2 Cl.sub.2 /CH.sub.3                                           OH 9:1    30        0 #STR151##       (R&S) cPent                                 R-Gly     0.18 C/EA 1:1    31        0 #STR152##       (R&S) cPent                                 Bn        0.15 C/EA 7:3    32        0 #STR153##       (R&S) cHept                                 R-Gly     0.21 C/EA 1:1    33        0 #STR154##       (R&S) cHept                                 Bn        0.22 C/EA 7:3    34        1 #STR155##       (R&S) cPent                                 R-Gly     0.27 CH.sub.2 Cl.sub.2 /CH.sub.3                                           OH 95:5    35        1 #STR156##       (R&S) cPent                                 Bn  173-174    36        1 #STR157##       (R&S) cHept                                 R-Gly     0.25 CH.sub.2 Cl.sub.2 /CH.sub.3                                           OH 95:5    37        1 #STR158##       (R&S) cHept                                 Bn  175-176    38        2 #STR159##       (R&S) cPent                                 R-Gly     0.28 CH.sub.2 Cl.sub.2 /CH.sub.3                                           OH 95:5    39        2 #STR160##       (R&S) cPent                                 Bn  146    40        2 #STR161##       (R&S) cHept                                 R-Gly     0.03 CH.sub.2 Cl.sub.2 /CH.sub.3                                           OH 95:5    41        2 #STR162##       (R&S) cHept                                 Bn  186    42        3 #STR163##       (R&S) cPent                                 R-Gly     0.31 CH.sub.2 Cl.sub.2 /CH.sub.3                                           OH 95:5    43        4 #STR164##       (R&S) cPent                                 R-Gly     0.3 CH.sub.2 Cl.sub.2 /CH.sub.3 OH                                           95:5    44        5 #STR165##       (R&S) cPent                                 Bn        0.4 C/EA 4:6    45        5 #STR166##       (R&S) cHept                                 R-Gly     0.2 CH.sub.2 Cl.sub.2 /CH.sub.3 OH                                           95:5    46        6 #STR167##       (R&S) cPent                                 Bn        0.21 C/EA 4:6    47        6 #STR168##       (R&S) cHept                                 Bn  172    48        7 #STR169##       (dia A) cPent                                 R-Gly     0.37 CH.sub.2 Cl.sub.2 /CH.sub.3                                           OH 100:10    49        7 #STR170##       (dia B) cPent                                 R-Gly     0.37 CH.sub.2 Cl.sub.2 /CH.sub.3                                           OH 100:10    __________________________________________________________________________

We claim:
 1. A heterocyclically substituted phenylglycinolamide of theformula (I) ##STR171## in which A represents a radical of the formula##STR172## in which R³ and R⁴ are identical or different and denotehydrogen, phenyl halogen, formyl, carboxyl, straight-chain or branchedalkoxycarbonyl having up to 4 carbon atoms or straight-chain or branchedalkyl having up to 4 carbon atoms, which is optionally substituted byhydroxyl,R⁵ denotes phenyl or alkylthio having up to 6 carbon atoms,inwhich R¹ represents cycloalkyl having 3 to 8 carbon atoms, or representsstraight-chain or branched alkyl having up to 10 carbon atoms, R²represents a radical of the formula ##STR173## in which R¹³ denoteshydrogen or a radical of the formula CH₂ --OH, R¹⁴ denotes phenyl whichis optionally substituted up to 3 times identically or differently byhydroxyl, halogen or straight-chain or branched allyl having up to 5carbon atoms, or a salt thereof.
 2. The heterocyclically substitutedphenylglycinolamide of the formula according to claim 1in which Arepresents a radical of the formula ##STR174## R³ and R⁴ are identicalor different and denote hydrogen, phenyl fluorine, chlorine, bromine,formyl, straight-chain or branched alkoxycarbonyl having up to 3 carbonatoms or straight-chain or branched alkyl having up to 3 carbon atoms,which is optionally substituted by hydroxyl, R⁵ denotes phenyl oralkylthio having up to 5 carbon atoms, R¹ represents cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or representsstraight-chain or branched alkyl having up to 8 carbon atoms, R²represents a radical of the formula ##STR175## in which R¹³ denoteshydrogen or a radical of the formula CH₂ --OH, R¹⁴ denotes phenyl whichis optionally substituted tip to 2 times identically or differently byhydroxyl, fluorine, chlorine, bromine or straight-chain or branchedalkyl having up to 3 carbon atoms, or a salt thereof.
 3. Theheterocyclically substituted phenylglycinolamide of the formulaaccording to claim 1in which A represents a radical of the formula##STR176## in which R³ and R⁴ are identical or different and denotehydrogen, phenyl chlorine, formyl, methoxycarbonyl, ethoxycarbonyl ormethyl or ethyl, which is optionally substituted by hydroxyl, R⁵ denotesphenyl, methylthio, or ethylthio or a salt thereof.
 4. A composition forthe treatment of atherosclerosis comprising an amount effective thereforof a compound or salt thereof according to claim 1 and apharmacologically acceptable diluent.
 5. The method of treatingatherosclerosis in a patient in need thereof which comprisesadministering to such patient an amount effective therefor of a compoundor salt thereof according to claim
 1. 6. The compound2-cyclopentyl-N-(2-hydroxy-1-(R)-phenylethyl)-2-4-(2-phenylimidazol-1-yl-methyl)phenyl!acetamide of the formula##STR177## or a salt thereof.
 7. The compound2-cyclopentyl-N-(2-hydroxy-1-(R)-phenyl-ethyl)-2-4-(2-methylthio-imidazol-1-yl-methyl)phenyl!acetamide of the formula##STR178## or a salt thereof.